Stroke is the third leading cause of death in the US and is a leading cause of disability. However, current treatments do not help the majority of patients. To avoid the limitations of current treatments we are approaching stroke therapy in a different way. Current treatments focus on the early events that cause the initial stroke damage. Instead, we are turning to later pathological events that exacerbate the injury and may influence recovery as well. Specifically, inflammation occurs immediately after stroke and immune system activation can persist for several days or even weeks after stroke. Inhibiting inflammation by inhibiting cyclooxygenase (COX) enzymes improves stroke outcomes in animal models, even when COX inhibitors are given many hours after the stroke began. However, COX inhibition is not a viable therapeutic strategy in humans because of unacceptable side effects. We and others have identified the EP2 receptor as a downstream mediator of many of the toxic effects of COX. However, the EP2 receptor is unlikely to play a role in the side effects of COX inhibition. Thus, we hypothesize that inhibiting the EP2 receptor will mimic the beneficial effects of inhibiting COX without the negative side effects. If our hypothesis is true then EP2 inhibitors may be extremely valuable as a new type of therapy for stroke. We will test our hypothesis by using novel genetic and pharmacological tools to inhibit EP2 signaling. Our genetic experiments will employ mice lacking EP2 receptor expression in myeloid cells, a population of cells responsible for many of the relevant immune responses. These experiments will allow us to clearly delineate the cell-specific effects of EP2 signaling after stroke. We will also employ a complementary pharmacological approach. Our collaborators have developed a novel, brain-penetrant and specific EP2 antagonist that we will use to determine the optimal time window for EP2 antagonist treatment after stroke. For both genetic and pharmacological experiments we will quantify stroke outcomes with or without EP2 inhibition and we will quantify the mechanistic effects of EP2 inhibition on inflammation. Our experiments will evaluate the role of EP2 signaling during stroke-induced inflammation and may illuminate new opportunities for the treatment of stroke.